The Role of Liver Disease in Alcohol-Induced Cognitive Defects.

Chronic severe liver disease (i.e., cirrhosis) is a common complication of chronic alcohol abuse. Cirrhosis can cause brain dysfunction, most notably the disorder portal-systemic encephalopathy (PSE), which is characterized by cognitive and motor dysfunction and, eventually, by hepatic coma. Restoration of normal liver function-for example, through liver transplantation-can reverse some of the symptoms of PSE. PSE is caused by the shunting of venous blood into the general circulation without prior detoxification in the liver, allowing neurotoxins to reach the brain. The most prominent neurotoxin is ammonia. It interferes with the function of different brain cells and the communication between them. Ammonia and other toxins reaching the brain in PSE patients affect several neurotransmitters, including glutamate and monoamines.

C ognitive dysfunction is common gests that alcoholinduced liver disease This article focuses on the symptoms among alcoholics; up to 75 per also plays an important role in precipitat and causes of the most prevalent liver cent of detoxified longterm ing the cognitive impairment encountered diseaseassociated brain dysfunction, alcoholdependent patients show in alcoholdependent patients and com portalsystemic encephalopathy (PSE). symptoms of cognitive impairment (Arria pounds the alcohol's neurotoxic effects. Although PSE also can be the conse et al. 1990). Several factors have been For example, alcoholics with cirrhosis quence of nonalcoholic liver disease (i.e., proposed to contribute to alcoholinduced exhibit greater impairment in writing speed cirrhosis), at least 50 percent of PSE cases cognitive dysfunction. They include direct and reaction times than do alcoholics with result from alcoholic cirrhosis. Therefore, toxic effects of alcohol on nerve cells; out liver disease (Gilberstadt et al. 1980). unless specifically mentioned otherwise, compromised nutritional status (particularly Similarly, when brain functions of alco terms such as "liver damage" or "cirrho thiamine [i.e., vitamin B] deficiency; see holics with and without cirrhosis were sis" refer to both the alcoholic and nonal article by Langlais,; and studied by such methods as measuring the coholic disorder. In alcoholdependent alcoholinduced damage to other organs, blood flow through the brain or performing such as the liver.
an electroencephalogram (EEG), patients ROGER F. BUTTERWORTH, PH.D., is direc Chronic alcohol abuse is the most with cirrhosis showed greater impairment tor of the Neuroscience Research Unit at important cause of liver disease in the than did patients without liver disease Hôpital SaintLuc and professor of United States. For example, about two (Tarter et al. 1993 PSE patients, however, it is assumed PSE results from alcoholinduced liver damage. This article describes how liver dysfunc tion may lead to PSE by causing alterations in several pathways of communication between nerve cells. The article also ad dresses the effectiveness of one potential treatment-liver transplantation-for liver disease and the PSE resulting from it.

PORTALSYSTEMIC ENCEPHALOPATHY
PSE, which is a common complication of cirrhosis (Butterworth 1994a), develops slowly and progresses through several distinct clinical stages that are character ized by specific cognitive and neuromus cular symptoms (table 1). The earliest symptoms include alterations of sleep patterns, reduced attention span, anxiety, depression, and muscle incoordination. As the condition progresses, additional symp toms appear, such as personality changes, memory loss, asterixis, 1 confusion, stupor, and muscle rigidity. The disorder's final stage is characterized by hepatic coma. The progression of PSE, which can hap pen rapidly, can be brought on by various factors, such as deterioration of the pa tient's general health, gastrointestinal bleeding, infections, kidney failure, or use of sedative drugs (Arria et al. 1990).
As a result of the wide spectrum of psychiatric and neuromuscular symptoms encountered in alcoholdependent patients with PSE, physicians often fail to diag nose the disorder correctly or even to recognize alcohol's contribution to the development of the disorder. In the past, misdiagnoses have included depression, schizophrenia, mild forms of mania, and Parkinson's disease (Tarter et al. 1986). The PSE diagnosis is complicated further by the fact that not all patients with PSE have obvious signs of liver disease and abnormal liver test results. Therefore, a physician may attribute brain dysfunction symptoms in alcoholdependent patients to alcohol's direct neurotoxic effects on the brain rather than to the involvement of alcoholic liver disease.

Subclinical PSE
Prior to the development of overt PSE, many patients with less severe liver dam age suffer from latent or subclinical PSE. These patients show no obvious clinical signs of brain dysfunction during routine neurological evaluation. Sensitive neuro psychological tests, however, can detect subtle signs of cognitive impairment (e.g., impaired memory capacity or psychomo tor performance). Therefore, neuropsy chological tests should be performed routinely on patients with severe liver damage, especially because abnormal test results may indicate a risk for impaired performance-for example, while driving an automobile (see below).
The fact that the liver disease, whether alcohol induced or nonalcoholic, contrib utes to the development of subclinical PSE has been demonstrated in several studies, as described below: • Schomerus and colleagues (1981) compared the performance of 40 pa tients with either alcoholinduced or nonalcoholic cirrhosis with a control group of patients with alcoholic pancre atitis in a battery of tests of cognitive and motor function used to assess the ability to drive an automobile. Whereas 80 percent of patients with alcohol induced cirrhosis were considered unfit to drive, only 25 percent of the patients with alcoholic pancreatitis had the same level of impairment. Patients with alcoholic cirrhosis consistently were more impaired than were patients with nonalcoholic cirrhosis; however, the difference in impairment was due to a greater degree of liver dysfunction rather than to the duration and quantity of previous alcohol consumption among the alcoholic patients.
• Tarter and colleagues (1984a) found that patients with nonalcoholic cirrho sis showed no overt symptoms of PSE but exhibited impaired visual scanning abilities, visuospatial capacity, and perceptual motor speed when more sensitive tests of cognitive functioning were used.

CAUSES OF PSE
PSE is caused by the shunting of venous blood, which contains metabolic products from the intestine, into the general circu lation without passing through the liver first. The liver normally removes toxic substances and metabolic products from the blood (for more information on nor mal liver function, see sidebar p. 127). Consequently, if venous blood is shunted around the liver, toxic substances can reach other parts of the body, including the brain. One common neurotoxin is ammo nia, which primarily is produced as a byproduct of protein digestion. Another potential toxin usually removed by the liver is the metal manganese (Pomier Layrargues et al. 1995). The accumulation of ammonia and other substances, such as manganese, in the brain may interfere with the actions of different neurotransmitters that mediate normal communication between nerve cells. Through this interference, these substances, and especially ammonia, con tribute to the cognitive and neuromotor symptoms associated with PSE. Under normal circumstances, venous blood is transported to the liver through the portal vein ( figure 1A). Before reaching the liver, the portal vein crosses another major vein, the inferior vena cava, which transports unoxygenated blood from the lower limbs and the abdomen to the heart. In patients with alcoholinduced or nonal coholic cirrhosis, pressure in the portal vein is increased due to obstructions in the liver. This phenomenon is referred to as portal hypertension. Portal hypertension can result in lifethreatening complica tions, such as gastrointestinal bleeding.
Portal hypertension can lead to the shunting of blood from the portal vein into the inferior vena cava through two mechanisms (figure 1B and 1C). First, portal hypertension can cause the dilation (i.e., widening) of minuscule blood ves sels, socalled collateral veins, that con nect the portal vein and the inferior vena cava. This allows some ammoniarich blood to enter the general circulation without passing through the liver and to reach the brain.
Additionally, in patients with severe portal hypertension, shunts between the portal vein and the inferior vena cava may have to be created through surgery to relieve the hypertension. One such proce dure-called portacaval anastomosis-that creates a shunt outside the liver is depicted in figure 1C. Another more recent tech nique that is gaining popularity is the transjugular intrahepatic portosystemic stent shunt (TIPS), which creates a shunt inside the liver. Both surgical techniques cause ammoniarich blood from the portal vein to enter the general circulation. This leads to PSE in up to 30 percent of patients treated with TIPS. For example, in one study of 108 patients with alcoholinduced and nonalcoholic cirrhosis, TIPS treatment precipitated or worsened PSE in 24 percent of the patients. Eleven patients required hospitalization because of severe PSE; 3 patients even fell into hepatic coma and died (Skeens et al. 1995). Thus, PSE can be the consequence of liver disease per se or can be caused or exacerbated by a life saving surgical procedure designed to prevent the immediate danger of poten tially fatal hemorrhage.

The Role of Ammonia in PSE
As mentioned earlier, the concentration in the brain of the neurotoxin ammonia rises as a consequence of severe liver dysfunc tion. The contribution of excess ammonia to the development of PSE recently has been demonstrated by an imaging tech nique called positron emission tomography (PET). This technique allows scientists to monitor the metabolism of different sub stances in the brain. PET studies in alco holics with cirrhosis and early stages of PSE revealed that compared with healthy subjects, the brain in alcoholics showed increased uptake and removal of ammonia (figure 2; Lockwood et al. 1991). Ammonia exerts its toxic effects on the brain through several mechanisms. For example, ammonia concentrations similar to those achieved in laboratory animals with experimentally induced liver failure directly interfere with both inhibitory and excitatory neurotransmitter systems in the brain (Raabe 1989;Fan et al. 1990). (For a more detailed discussion of different trans mitter systems, see sidebar, p. 128.) Chronic exposure of the brain to am monia also causes structural and func tional changes in specific brain cells called astrocytes. These cells, among their other functions, are involved in the metabolism of neurotransmitters and other substances Surgical treatment of portal hypertension, called end-to-side portacaval anastomosis, connects the portal vein directly to the inferior vena cava to reduce the pressure in the portal vein. Ammonia-rich blood from the intestine now gains free access to the general circulation. The portal collateral veins shrink. Alcoholic cirrhotic liver. The liver takes on a nodular appearance. Pressure in the portal vein increases and causes the widening of collateral veins. Thus, some ammonia-rich blood reaches the general circulation.
Normal liver. All ammonia-rich blood from the intestine is carried to the liver via the portal vein.  .
In addition, evidence suggests that chronic liver disease and the resulting accumulation of neurotoxins, such as ammonia, in the brain contribute to PSE development by interfering with the actions of other neurotransmitters. For example, early PSE symptoms include altered sleep patterns, personality changes, depression, and paranoia. These symptoms have been attributed in part to the dysfunction of neurotransmitters called monoamines, such as serotonin or dopamine. Consistent with these observa tions, researchers have detected changes in the metabolism of monoamine neuro transmitters in patients with PSE.

Serotonin Deficiency
Several studies indicate that PSE patients have a serotonin deficit in the brain, which may contribute to the PSE symp toms. For example, PSE patients with alcoholinduced cirrhosis who died in hepatic coma showed a significant in crease in the numbers of receptors for serotonin on nerve cells in some areas of their brains (Raghavendra Rao and Butterworth 1994). Such an increase in receptor numbers often occurs when the concentration of the ligand (i.e., the sub stance binding to the receptor) is too low. The increase may reflect the organism's effort to saturate the cells with binding sites so that every last ligand molecule can be bound. Consequently, an increase in serotonin receptors may be indicative of a serotonin deficiency in the brains of PSE patients.
Clinical data also support a serotonin deficit in PSE patients: When patients with cirrhosis, but without PSE, received the serotonin antagonist ketanserin to lower their portal hypertension, 2 a signifi cant number of them developed PSE (Vorobioff et al. 1989). Ketanserin inhib its the binding of serotonin to its receptor and thus mimicks a serotonin deficiency. If this artificial serotonin deficiency can lead to PSE, then a cirrhosis induced serotonin deficiency also may contribute to PSE.
The mechanisms underlying changes in serotonin levels have not been resolved conclusively. Ammonia levels are one factor affecting serotonin levels: In order to remove toxic ammonia from the brain, it is incorporated into the amino acid glutamine (Jonung et al. 1983). Elevated ammonia concentrations therefore result in higher glutamine concentrations. Gluta mine, in turn, facilitates the uptake of the amino acid tryptophan, which is a precur sor molecule of serotonin (Jonung et al. 1983). When analyzing the serotonin metabolism of patients in hepatic coma, researchers found that tryptophan levels are higher than normal in both the brain and the cerebrospinal fluid (CSF) (Young et al. 1975).
Conversely, a study by Bergeron and colleagues (1990) detected increased concentrations of a serotonin degradation product in both the brain and CSF of PSE patients with cirrhosis and in the brains of laboratory animals with experimentally induced PSE. This increase already is apparent early in the progression of neu rological symptoms of PSE. The increase in the levels of both serotonin precursors and serotonin degradation products indi cates that in the brains of PSE patients, serotonin may be produced at a higher rate but is degraded even faster. Com bined, these two processes could result in lower overall levels of serotonin in the patients' brains.

Impaired Dopamine Function
The normal function of the neurotransmit ter dopamine also appears to be affected in PSE patients (Bergeron et al. 1989). Alterations of dopaminemediated neuro transmission are the most likely causes of the motor impairment (e.g., tremor and rigidity) that sometimes is observed in PSE patients. Researchers have discovered a significant loss of dopamine receptors on the postsynaptic cells in the pallidum (a brain structure involved in motor con trol) of PSE patients (Mousseau et al. 1993). Also, using magnetic resonance imaging (MRI), Kulisevsky and colleagues (1992) found an enhanced signal in the pallidum of PSE patients (figure 3). One possible cause for the MRI signal is the accumulation of manganese in the brains of these patients (Pomier Layrargues et al. 1995). Manganese is known to be toxic to dopaminergic neu rons (Bird et al. 1984). Shown are PET images of the cerebral blood flow (CBF; a measure of brain function), the cerebral metabolic rate for ammonia (CMRA; the rate with which the brain takes up and removes ammonia), and the permeability/surface area product (PS; a parameter that reflects how easily ammonia can enter the brain) from a healthy subject and a cirrhotic patient with mild PSE. (From Lockwood et al. 1991, with permission.) Healthy Subject

NEUROPSYCHIATRIC STATUS AFTER LIVER TRANSPLANTATION
Cirrhotic Patient PS Liver cirrhosis is a permanent disorder that cannot be reversed except by liver transplantation. Several studies have investigated whether liver transplantation can reverse PSE symptoms. In an early study, Parkes and colleagues (1970) com pared the neuropsychiatric status and brain activity before and after transplantation in four patients with serious liver disorders, one of them with chronic PSE. All patients showed striking and lasting clinical im provement of their cognitive impairments as well as normalization of their EEG patterns following liver transplantation. Tarter and colleagues (1984b) evalu ated the cognitive and psychiatric status of 10 patients with nonalcoholic cirrhosis 3 years after successful liver transplanta tion. In all patients, measures of intelli gence, verbal skills, attention, spatial organization, memory, and learning had improved after transplantation. In a simi lar study, Arria and colleagues (1991) compared the cognitive functioning of patients with alcoholic cirrhosis shortly before and 1 year after liver transplanta tion. Most of the patients showed signifi cant improvement in their psychomotor function, visuospatial capacity, attention, and perception skills. Tests assessing their memory capacity, however, showed no significant improvement, indicating that nonliver diseaserelated factors may be responsible for memory impairment.
These results confirm that alcohol induced liver disease contributes to cogni tive dysfunction in alcoholics and that in many patients, this dysfunction is at least partially reversible-for example, by liver transplantation. Some aspects of cognitive impairment may not be reversible by the normalization of liver functions if factors other than liver disease, such as alcohol's neurotoxicity or alcoholinduced thiamine deficiency (see article by Langlais,, have contributed to the impair ment of these cognitive functions.

CONCLUSIONS
PSE is a complication of both alcoholic and nonalcoholic cirrhosis that results in cognitive impairment (including attention deficits, personality changes, memory loss, and confusion) and neuromuscular impair ment (including incoordination and tremors). In alcoholics, cirrhosis and the PSE result

LIVER FUNCTION AND ALCOHOLINDUCED LIVER DISEASE
The liver is the largest internal organ Institute on Alcohol Abuse and Alcohol of the human body. It performs several ism [NIAAA] 1994). For example, a vital functions in the digestion, process person's gender, race, and genetic ing, and storage of nutrients and in the makeup seem to be contributing factors. excretion of waste. One important liver Similarly, the duration and quantity of function is the removal of harmful or alcohol consumption contribute to the toxic substances from the body. These risk for liver disease. include toxins that may be contained in During alcohol metabolism, some some foods; toxic degradation products potentially toxic degradation productsof nutrients; and other toxins, such as such as acetaldehyde or highly reactive pesticides and alcohol and other drugs.
oxygen molecules (radicals)-are gener In many cases, liver enzymes will ated. In addition to alcohol itself, these break down or transform toxic sub products contribute to alcoholinduced stances into less harmful products, liver damage. which then can be either returned into Alcoholic liver disease usually the circulation or excreted in the urine. progresses in three distinct stages, de Other toxins, however, cannot be scribed below: degraded or detoxified because the liver is lacking the appropriate en • Fatty liver or alcoholic steatosis: This zymes. These toxins (e.g., the pesti initial stage of liver injury is found cide DDT) are then stored in the liver.
in about 90 percent of heavy drinkers One of the toxins normally elimi (NIAAA 1994). Fatty liver is a rever nated by the liver is ammonia. It is sible condition that is accompanied produced in the body primarily as a by only slight tissue damage. At this degradation product in the metabolism stage, little evidence of liver dysfunc of dietary proteins and their building tion is detected. blocks, the amino acids. Ammonia is transported in the unoxygenated ve • Alcoholic hepatitis and fibrosis: These nous blood from the intestinal region two disorders, which can be found in to the liver through the portal vein. In about 40 percent of heavy drinkers the liver, the ammonia is transformed (NIAAA 1994), represent more serious into urea, which is less toxic than conditions than fatty liver. They are ammonia and can be excreted safely associated with increasing destruction with the urine.
of liver tissue and, consequently, with increasing liver dysfunction. Alcoholic hepatitis results in inflammation and

ALCOHOL AND LIVER DISEASE
destruction of the liver tissue. In alco holic fibrosis, healthy liver tissue is The liver also is the primary site for replaced by scar tissue. alcohol metabolism. Consequently, the liver is highly susceptible to alcohol induced injury. The susceptibility of SUSANNE HILLERSTURMHÖFEL, PH.D., is a person to alcoholic liver disease is a science editor of Alcohol Health & determined by several factors (National Research World. • Alcoholic cirrhosis: This final stage of alcoholinduced liver disease is diagnosed in 15 to 30 percent of heavy drinkers (NIAAA 1994). A cirrhotic liver is characterized by heavily scarred liver tissue and a lumpy (nodular) appearance.
Coinciding with the structural damage is severe dysfunction, which in turn can impair the func tioning of other organs and con tribute to disorders such as kidney failure; gastrointestinal bleeding; and brain disorders, including portalsystemic encephalopathy.
The treatment of alcoholic liver disease first and foremost requires abstinence from alcohol to prevent further damage. Because the liver has the capacity to regenerate itself (Diehl 1993), some patients may recover from alcoholinduced liver damageespecially in the early stages-without further treatment. For patients with endstage cirrhosis, however, liver transplantation may be the only treat ment option (NIAAA 1994 ing from it compound the toxic effects that alcohol exerts directly on the brain. Because cirrhosis is a chronic disorder, alcoholic cirrhosis may perpetuate and magnify alcoholinduced cognitive im pairment even after the patient stops drinking (Tarter et al. 1993). However, reversal of the liver dysfunction-for example, through liver transplantationcan result in the normalization of many cognitive deficits. In addition, treatment with ammonialowering drugs, such as lactulose and the antibiotic neomycin, usually improves PSE symptoms in pa tients with less severe liver dysfunction.
During the last decade, much interest has focused on the possibility that endoge nous compounds with benzodiazepine (valium)like properties, which are pre sent in the blood and brains of a subgroup of PSE patients, may contribute to PSE (Olasmaa et al. 1990). This hypothesis has led to clinical trials in which PSE patients were treated with flumazenil, a drug with potent antibenzodiazepine effects. Up to 30 percent of the patients responded positively to flumazenil administration (Pomier Layrargues et al. 1994).
PSE is characterized by many diverse symptoms, which also resemble the conse quences of other disorders; as a result, the disorder often is not diagnosed correctly. Therefore, physicians should carefully

SIGNAL TRANSMISSION AMONG NERVE CELLS
Communication or signal transmission among nerve cells (neurons) or be tween neurons and the cells of other organs underlies such diverse functions as movement or thought. This com munication is achieved through a combination of electric and chemical processes. Within a neuron, an electric signal travels along the length of the cell. Between cells, molecules called neurotransmitters primarily mediate signal transmission.

SIGNAL TRANSMISSION ACROSS SYNAPSES
Neurons generally are separated from each other by microscopic gaps called synapses. Accordingly, a cell emitting a signal is referred to as a presynaptic cell; a cell receiving a signal is called a postsynaptic cell. Although synapses are very small, they cannot be crossed by an electric signal, and neurotrans mitters are used to convey the signals. Neurotransmitters are stored in small vesicles in the presynaptic nerve cell ending. Although there are different neurotransmitters in the body, each neuron releases predominantly one kind of neurotransmitter.
When an electric signal arrives at the end of the presynaptic cell, the storage vesicles discharge their neuro transmitter contents into the synapse. The molecules diffuse across the synapse to the postsynaptic cell. This cell's membrane contains protein molecules called receptors, to which the neurotransmitters can bind. Each receptor is shaped so that it only binds one specific neurotransmitter; however, several different receptor molecules may exist for each neurotransmitter. Also, each cell may contain receptors for several neurotransmitters.
Neurotransmitters bind to their receptors without actually entering the postsynaptic cell. The binding reaction triggers a chain reaction of events in the postsynaptic cells. The reaction is terminated when the neuro transmitter dissociates from its receptor to be degraded or to be taken back up into storage vesicles in the presynaptic cell.

NEUROTRANSMITTERS
As mentioned earlier, several different neurotransmitters exist. They fall into categories according to their effects on the postsynaptic cells or according to their chemical structure.
Neurotransmitters can have an excita tory or inhibitory effect on the postsynap tic cell. Excitatory neurotransmitters may stimulate the cell to produce an electric signal of its own, thus transmitting the incoming signal further along the cell and to adjacent cells. Inhibitory neurotransmit ters, in contrast, reduce the postsynaptic cell's sensitivity to other incoming signals, thereby preventing further signal trans mission. Each postsynaptic cell receives signals from many other neurons. Some signals are transmitted by excitatory neu rotransmitters and others by inhibitory ones. The ultimate response of the post synaptic cell depends on the combined effect of all signals.
Several substances can function as neurotransmitters. Many of them are small molecules that rapidly transmit signals among nerve cells and to other cells, such as muscle cells. These neuro transmitters can be subgrouped according to their chemical structure into several categories, three of which (described below) are most prevalent in the body and may mediate alcohol's effects.
• Acetylcholine, one of the most com mon neurotransmitters, is in a group by itself. It is secreted by many neu rons in the brain and also by neurons innervating the muscles. In most cases, acetylcholine has an excita tory effect on the postsynaptic cell.
• Monoamines are compounds that contain a characteristic chemical group. Several of these substances function as neurotransmitters, includ ing dopamine and serotonin. Dopa mine usually has an inhibitory effect on the postsynaptic cells. Neurons using dopamine as a transmitter are involved in controlling motor activ ity and the rewarding effects of abused drugs, such as alcohol. Serotoninmediated transmission affects mood, sleep, the consump tion of drugs, the development of tolerance to alcohol and other drugs, and the sensation of pain.
• Some amino acids not only are building blocks of proteins but also function as neurotransmitters. One example is glutamate, which serves as an excitatory neurotrans mitter for sensory signals.
The accurate functioning of all neurotransmitter systems is essential to ensure the normal brain activities required for every aspect of human body function. Alcohol interferes with the intricate network of neural signal transmission through numerous path ways, thus causing the cognitive and motor impairments that are observed in many alcoholdependent people (National Institute on Alcohol Abuse and Alcoholism 1994).
-Susanne HillerSturmhöfel assess liver function in all alcoholics with neuropsychological impairment.
Although it seems clear that the failure of the liver to remove toxic ammonia from the blood is an important factor in precipi tating PSE, the exact mechanisms of how ammonia affects brain functions still require further investigation. Furthermore, the contribution of alterations in the func tions of different neurotransmitters (i.e., monoamines and others) to the symptoms and consequences of PSE are not known in detail. A better understanding of the molecular processes involved may open new avenues to treating cognitive impair ment in alcoholic patients.
Similarly, it is important to study other aspects of alcoholic liver disease that may contribute to PSE. For example, it has been suggested that liver dysfunction may lead to nutritional vitamin deficiencies, including vitamin E and some B vitamins (Butterworth 1994b). Alcoholrelated deficiencies in these vitamins have been implicated in several neuropsychological and neuromotor dysfunctions in alcohol ics (Arria et al. 1990(Arria et al. , 1991. Together, these findings underscore the importance of looking beyond the neurotoxic actions of alcohol per se when trying to identify the causes of cognitive impairment in alcoholic patients. ■